Human butyrylcholinesterase efficacy against nerve agent exposure

Abstract

Acetylcholinesterase is vital for normal operation of many processes in the body. Following exposure to organophosphorus (OP) nerve agents, death can ensue without immediate medical intervention. Current therapies mitigate the cholinergic crisis caused by nerve agents but do not fully prevent long-term health concerns, for example, brain damage following seizures. Human butyrylcholinesterase (HuBChE) is a stoichiometric bioscavenger being investigated as an antidote for OP nerve agent poisoning. HuBChE sequesters OP nerve agent in the bloodstream preventing the nerve agent from reaching critical target organ systems. HuBChE was effective when used as both a pre-treatment and as a post-exposure therapy. HuBChE has potential for use in both military settings and to protect civilian first responders in situations where nerve agent usage is suspected. We reviewed various animal models studies evaluating the efficacy of HuBChE against nerve agent exposure, pursuant to its submission for approval under the FDA Animal Rule.

Structure and therapeutic uses of butyrylcholinesterase: Application in detoxification, Alzheimer's disease, and fat metabolism

“…In 1943, Richard Kuhn determined that the acute toxicity of OPs was caused by the rapid phosphorylation of AChE, which led to the accumulation of ACh in the synaptic clefts and overstimulation of ACh receptors and finally induced cholinergic crisis 48,49 . Clinical effects of OPs poisoning include increased gastrointestinal motility, nausea, anxiety, and confusion 47 …”

“…BChE and its various derivatives have been well developed in all three types. Additionally, BChE has been considered as the most promising bioscavenger 49 due to its safety, high reaction effectiveness with a broad spectrum of existing OPs and long biological half‐life. Actually, native BChE existing in human plasma acts as a natural defense against low dose OPs.…”

“…Similarly, BChE protein complexed with OPs would also not result in adverse effects on circulating AChE activity, organs and behavior 79 . Additionally, Phase 1 and 2 pharmacokinetic (PK) and safety studies of hu BChE in humans have already been completed 49 …”

A primer on nerve agents: what the emergency responder, anesthesiologist, and intensivist needs to know

“…In one study, human butyrylcholinesterase was effective as both a pretreatment and as a postexposure therapy. 73 There is additional work being performed on the development of improved oximes, such as HI-6, for use in the United States and other countries.…”

Steady-State Kinetics of Enzyme-Catalyzed Hydrolysis of Echothiophate, a P–S Bonded Organophosphorus as Monitored by Spectrofluorimetry

“…Thus, to drop a concentration in echothiophate of 3 × 10 −6 M by 100-fold (ln[OP] 0 /[OP] t = 4.6) in human blood in 1min (median time for a full turn of blood circulation), an amount of 9 mg of GG1 would be needed to inject to a human of 70 kg. Such a dose is about 20-fold lower than the equivalent dose that would be needed with a stoichiometric bioscavenger like human BChE [40,41]. Decontamination of biological samples or fragile materials by GG1 would also be very effective and fast.…”